This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fuchs endothelial corneal dystrophy (FECD;MIM136800) is a common eye disease, affecting approximately 1% of the general US population. Initially asymptomatic, individuals eventually present with decreased vision, foreign body sensation and pain upon waking. Slit lamp (microscopic) examination initially shows focal thickenings of Descemet's membrane known as corneal guttae, with subsequent stromal edema (swelling), epithelial edema and, in advanced stages, painful bullous keratopathy. FECD is a the most common inherited disease in the USA leading to corneal transplantation. In addition, individuals undergoing cataract surgery with FECD are at significant risk for corneal decompensation, requiring subsequent corneal transplantation. Molecular data on the genetic basis of corneal dystrophies is limited. With a significant population at risk, the identification of the gene(s) that may contribute to the dystrophy would be very useful for counseling, implementation of standard methods for therapeutic intervention, and ultimately gene modulation and/or therapy. In this study, we have used the network built by the active, multi-center NEI-funded Cornea Donor Study (CDS) as the nexus to identify families with FECD using the consortium model. We have nearly completed the recruitment phase of the project. We have identified cases with advanced FECD and will characterize the extent of familial clustering using a clinical measure of severity as a semi-quantitative trait. Family history, clinical, and other demographic information is being collected using a standardized instrument. Histopathologic confirmation of advanced index cases is being obtained. Blood samples are being collected for molecular genetic analyses. A web-based database has been constructed to facilitate multi-site data collection. A genome-wide scan will be conducted utilizing DNA collected from the index cases and families (432 families containing 658 sibling pairs, including 367 affected sib pairs, plus 69 unrelated cases). A genomewide association analysis will be performed utilizing approximately 500 unrelated cases--probands of families and unrelated cases--and 500 controls. We have so far collected 270 unrelated controls. In addition, model-free linkage analysis, using the SIBPAL program in S.A.G.E., will be conducted using the DNA marker data in conjunction with the clinical data on FECD to identify linkage signals. We are about to begin an initial association study on candidate genes identified through previous investigations of a limited number of families. Thus, we will investigate the importance of these genes on a more global basis by characterizing their role in a larger sample. We anticipate that this study will lead to novel insights into the etiology of FECD and the biology of the corneal endothelium.
Showing the most recent 10 out of 922 publications
